Nature chemical biology · 2026
GCN5-ERK lactylation-phosphorylation loop amplifies lactate-driven cancer progression.
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Huang Bingsong, Jin Mingpeng, Cui Gaofeng, Wang Zhe, Wang Feng, Chen Mu, Zhu Lei, Li Yunxuan, Yang Xiaoning, Li Rui, Wu Jinhuan, Zhai Linhui, He Yiming, Yang Jie, Ding Xin, Wang Qianwen, Xv Zhen, Ouyang Yaobing, Li Jiale, Yang Yangbohui, Li Ke, Lou Zhenkun, Mer Georges, Zhang Jing, Chen Yuping, Yuan Jian, Zhong Chunlong
Аннотация
The Warburg effect leads to increased lactate production and promotes cancer progression but the underlying mechanisms remain unclear. Here, we found that lactate activates the MAPK pathway through ERK lactylation, which promotes cancer progression. We identified GCN5 as the lactyltransferase responsible for ERK lactylation. Activated ERK phosphorylates GCN5, increasing its lactyltransferase activity toward ERK and establishing a positive feedback loop that amplifies lactate-mediated cancer progression. We provide evidence that lactylation of ERK at residue K231 weakens its interaction with MEK, thereby promoting ERK dimerization and activation. We developed a cell-penetrating peptide that specifically inhibits ERK lactylation. This peptide impairs tumor growth in KRAS-mutant cancer models. Taken together, our findings reveal a molecular mechanism by which lactate accelerates cancer progression through the ERK-GCN5 lactylation-phosphorylation cascade and suggest a strategy to disrupt ERK lactylation in RAS-ERK-driven cancers.